New antiemetic agents and multidrug regimens are available for the prophylactic treatment of chemotherapy-induced nausea and vomiting (CINV) and comprehensive antiemetic guidelines are available.1-4 Nevertheless, breakthrough CINV is a common clinical problem, affecting up to 40% of patients with cancer who are receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC).5 Dehydration and the resultant need for hydration therapy is a consequence of breakthrough CINV. The costs associated with breakthrough CINV can be substantial, including those associated with unscheduled hydrations.6
Granisetron extended-release (ER) subcutaneous (SC) injection is a novel formulation of first-generation granisetron that provides a therapeutic effect for 5 days after a single SC dose to prevent acute and delayed CINV.7 SC granisetron ER is administered as part of a guideline-recommended antiemetic regimen before chemotherapy.8,9 Palonosetron is a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist with a t1/2 of approximately 40 hours.10
Phase 3 clinical trials of combination antiemetic regimens have demonstrated the noninferiority of SC granisetron ER to palonosetron in the prevention of acute CINV associated with a MEC or a HEC regimen and in the prevention of MEC- and HEC-associated delayed CINV.11,12 In the Modified Absorption of Granisetron in the Prevention of CINV clinical trial—and as part of a 3-drug antiemetic regimen, including 5-HT3 receptor antagonist, fosaprepitant, and dexamethasone—SC granisetron was superior to ondansetron in the prevention of emesis or the need for rescue medication in HEC-associated delayed CINV.13
Palonosetron was approved in 2003 for the prevention of acute and delayed nausea and vomiting associated with MEC and the prevention of acute nausea and vomiting associated with HEC.14 SC granisetron ER was approved in 2016 for the prevention of acute or delayed CINV in patients receiving MEC or anthracycline and cyclophosphamide (ie, HEC) combination chemotherapy regimens.15 The National Comprehensive Cancer Network (NCCN) guidelines list SC granisetron and palonosetron as preferred 5-HT3 receptor antagonists, in combination with dexamethasone, for the prevention of MEC-associated CINV, and is a Category 1 recommendation, when combined with olanzapine, dexamethasone, and a neurokinin-1 receptor antagonist, for the prevention of HEC-associated CINV.1
CINV negatively affects patients’ overall health status, quality of life, and the ability to adhere to their prescribed course of chemotherapy.16-22 In addition, the impact of CINV extends to resource utilization and healthcare costs,21,23-25 which are affected by the associated need for rescue medication, hydration, correction of electrolyte imbalances, and hospitalization.1,5
Previously, our group performed a retrospective analysis to evaluate the requirement for CINV-related hydration among patients receiving SC granisetron or palonosetron for the prevention of MEC- or HEC-associated CINV in a community practice.26 Our study showed a significant benefit with SC granisetron versus palonosetron in reducing hydration requirements (mean hydration event, 0.3 vs 0.9, respectively; standard deviation, 0.6 vs 1.1, respectively; P <.0001).26 In addition, 78% of patients who received palonosetron required additional hydration 24 hours or more postchemotherapy through day 6 compared with 42% of patients who received SC granisetron.26
Based on the findings from the previous study, the goal of this current study was to analyze the impact of using SC granisetron versus palonosetron on the cost of unscheduled hydration associated with breakthrough CINV in patients receiving HEC or MEC.
This was a retrospective analysis of a multisite (24 locations) community-based practice, for which detailed methodology has been previously described.26 Briefly, consecutive patients with cancer were identified for data extraction from the electronic medical record system. These patients were scheduled to receive MEC or HEC and a recommended 3-drug antiemetic regimen—including a neurokinin-1 receptor antagonist, dexamethasone, and a 5-HT3 receptor antagonist—based on the NCCN antiemesis guidelines at the time of the clinic visit.27
The specific 5-HT3 receptor antagonists used included SC granisetron only, palonosetron only, or palonosetron that was switched to SC granisetron. In all cases, the dosing was 10 mg subcutaneously for SC granisetron ER and 0.25 mg intravenously for palonosetron, each administered with fosaprepitant 150 mg intravenously and dexamethasone 10 mg.26
As previously reported, hydration use (ie, the number of unscheduled hydration therapies per chemotherapy cycle) was compared between patients receiving SC granisetron only (N = 91) between October 2016 and June 2017; palonosetron only (N = 93) between January 2016 and June 2017; and patients who switched from palonosetron to SC granisetron between May 2016 and May 2017, because of a practice decision to use SC granisetron as the preferred 5-HT3 receptor antagonist for MEC and HEC regimens (N = 48).26
In performing the current cost analysis, we determined that 2 patients in the palonosetron-only group had been switched to SC granisetron, resulting in 91 patients who received palonosetron only being included in this current analysis. In the current cost analysis, we focused only on the patients receiving SC granisetron (N = 91) or palonosetron (N = 91), and did not include the patients who switched from palonosetron to SC granisetron (Table 1).
In evaluating the costs of care associated with unscheduled hydration, the components of care assessed (chemotherapy cycles 1-4; days 2-6 postchemotherapy), and the Current Procedural Terminology (CPT) codes for each component of care are summarized in Table 2.
We calculated the costs for each of these components, which were all based on the maximum per-unit Medicare reimbursement amounts (adjusted based on reimbursement rates from January 2016 through June 2017), and were subsequently totaled. We also performed an analysis by the type of chemotherapy received (ie, MEC or HEC).
The per-patient cost analysis for each component of care was calculated by the drug each patient received (ie, SC granisetron or palonosetron), as well as by whether the patients required additional components of care as a direct result of an unscheduled hydration visit, including hydration, rescue antiemetic drugs (SC granisetron or palonosetron), or fluids (potassium chloride per 2 mEq/mL saline 1000 mL, saline 500 mL, saline 250 mL), and drug administration, laboratory tests, and patient office evaluations.
All comparisons reported here were for the SC granisetron and palonosetron groups, excluding those who switched from palonosetron to SC granisetron. Nonparametric 2-sided Wilcoxon rank-sum tests were used to test the null hypothesis of no difference between the 2 groups in the costs of care.
A total of 182 patients were included in the study, 91 patients who received SC granisetron between October 2016 and June 2017, and 91 patients who received palonosetron between January 2016 and June 2017. Baseline demographic and clinical characteristics are summarized in Table 1. The study population was predominantly female (N = 128; 70%), with bronchus or lung cancer (N = 50; 27%) as the most common diagnosis.
In the group that received SC granisetron, 55 patients had received HEC and 36 patients had received MEC. In the group that received palonosetron, 76 patients had received HEC and 15 patients had received MEC. To account for the imbalances in the number of patients who received HEC and MEC between the 2 groups, a per-patient analysis was conducted.
All components of care related to unscheduled hydration clinic visits and their respective CPT codes used for the analysis are summarized in Table 2. The incurred per-patient costs for all components of care related to an unscheduled hydration visit in patients receiving HEC or MEC were significantly lower in the group that received SC granisetron than in the group that received palonosetron (mean, $296 vs $837, respectively; P <.0001; median, $0 vs $587, respectively; Table 3 and Appendix Figure 1).
The difference in the subset of patients who required additional hydration-related care (N = 39 for SC granisetron, N = 72 for palonosetron; Table 3) remained significant, because the cost for all components of care was lower for patients who received SC granisetron than for patients who received palonosetron ($692 vs $1058, respectively; P = .0260).
For the HEC group, those who received SC granisetron (N = 55) had a significantly lower per-patient cost associated with all components of care for unscheduled hydrations compared with patients who received palonosetron (N = 76; mean $343 vs $933, respectively; P <.0001; median, $0 vs $680, respectively; Table 4 and Appendix Figure 2A).
The same analysis of patients who received MEC resulted in lower per-patient costs in the 36 patients who received SC granisetron than in the 15 patients who received palonosetron (mean, $223 vs $348, respectively; P = .2219; median, $0 vs $182, respectively; Table 4 and Appendix Figure 2B).
Similar findings were observed in patients who required additional hydration-related care in the SC granisetron and palonosetron groups for HEC (N = 23; $823 vs N = 62; $1144, respectively) and for MEC (N = 16; $501 vs N = 10; $523, respectively).
In a further analysis of the costs for patients who required additional care at an unscheduled hydration, those who received HEC and SC granisetron had lower costs than patients who received HEC and palonosetron (maximum, $2504 vs $6595; median, $525 vs $856; mean, $823 vs $1144, respectively; Table 5).
A summary of the number of unscheduled hydrations and associated clinic visit costs, which were calculated using CPT codes 96360 and 96361, is shown in Table 6. For the HEC group, the number of unscheduled hydrations were lower in the SC granisetron group than in the palonosetron group (maximum, 16 vs 73, respectively; median, 3 vs 5, respectively; mean, 4 vs 8, respectively).
Similarly, the associated costs of unscheduled hydration when using CPT codes 96360 and 96361 were lower in the SC granisetron group (N = 22) than in the palonosetron group (N = 62; maximum, $452 vs $3297, respectively; median, $125 vs $228, respectively; mean, $166 vs $344, respectively). In addition, the costs for the patients who received MEC followed by SC granisetron were lower than for patients who received MEC followed by palonosetron; however, these differences were not significant (Table 6).
In this retrospective cost analysis of patients who received HEC or MEC at a community-based multisite clinic, the per-patient cost of care associated with unscheduled hydrations was lower for patients who received SC granisetron than for patients who received palonosetron. All components of the per-patient costs were lower among SC granisetron recipients than palonosetron recipients, with a particularly notable difference in the costs for unscheduled hydration between the 2 groups.
Furthermore, lower costs were incurred in patients who received SC granisetron compared with those who received palonosetron as part of a HEC regimen. In the subgroup of patients requiring additional care, lower costs and a lower total number of unscheduled hydrations were incurred after SC granisetron treatment compared with palonosetron treatment.
Palonosetron confers clinical and economic benefits over 5-HT3 receptor antagonists (including ondansetron, dolasetron, and granisetron).28,29 However, there are some conflicting data and remaining questions regarding its advantages over older agents.9 Given the results of our previously published primary analysis, in which the use of SC granisetron resulted in 3 times fewer CINV-related hydration events than palonosetron per chemotherapy cycle,26 a corresponding reduction in unscheduled hydration-related costs was expected.
In this current analysis, we also identified savings in other components of care that are a direct result of unscheduled hydration visits, including the costs for rescue antiemetic drugs and their administration, laboratory tests, and patient office evaluation.
Of note, in another retrospective study of hydration use in patients receiving SC granisetron or palonosetron in conjunction with MEC or HEC regimens, significant benefits were seen for SC granisetron versus palonosetron with respect to the mean scheduled hydration rate per treatment cycle (0.2 vs 0.6, respectively; P = .0005), as well as the proportion of patients requiring any hydration (33% vs 54%, respectively; P = .0033),30 which aligns with our primary findings.26
Overall, the results of the current cost analysis pertaining to unscheduled hydrations are consistent with, and expand on, previous observations regarding the propensity of inadequately controlled (ie, breakthrough) CINV to increase healthcare resource utilization and the associated costs, including those related to outpatient, inpatient, and emergency department care.21,23-25,31 Unscheduled hydration may be an additional suitable surrogate event for measuring breakthrough CINV that aligns with cost-effective cancer care.6
The results of a prespecified analysis of the De-ESCALaTE trial, which demonstrated superiority of cisplatin versus cetuximab with radiotherapy for head and neck cancer, lend further support to the importance of adequate hydration and antiemetic prophylaxis for HEC (cisplatin)-related CINV and dehydration.32 In that analysis, for which results have been presented but not yet published as of this writing, the use of triple antiemetic regimens postchemotherapy, intravenous fluids pre- and postchemotherapy, and oral fluids were all significant predictors of serious adverse events.32
New studies that further investigate 5-HT3 receptor antagonists and the association between complete response and unscheduled hydrations in patients receiving HEC or MEC regimens can be valuable to help achieve the optimal control of CINV.
We acknowledge that this analysis has several limitations, including those related to retrospective analyses based on data extraction from electronic medical records in real-world practice. Although the data were derived from 24 practice sites, they were all part of the same practice, which limits their generalizability.
Furthermore, the costs analyzed in this study are specific to the costs incurred in the outpatient setting (ie, hydration) and do not capture the costs of all the components of care of the emergency department or inpatient services.
In addition, the cost difference between SC granisetron and palonosetron for CINV prophylaxis was not included in this analysis, which focused on the costs of components of care (ie, rescue antiemetic drug administration, laboratory tests, and patient office evaluations) related to unscheduled hydration that resulted from breakthrough CINV.
The results of this analysis indicate that the use of SC granisetron versus palonosetron as a component of a 3-drug antiemetic regimen can reduce the need for unscheduled hydration in patients receiving HEC or MEC for breakthrough CINV. Similarly, it can reduce the need for additional concomitant care elements (ie, rescue antiemetic administration/drugs, laboratory tests, patient office evaluations), which can result in an overall lower per-patient cost of care related to unscheduled hydration in this patient population.
Medical writing support was provided by Phillip Giannopoulos, PhD, of SciStrategy Communications. Data aggregation facilitation was performed by Todd O’Connell of New York Cancer and Blood Disorders.
This study was funded by Heron Therapeutics, San Diego, CA.
Author Disclosure Statement
Dr Barnes, Mr Calcanes, and Dr Malik have no conflicts of interest to report. Dr Mosier has been a Consultant to Heron Therapeutics. Dr Vacirca has been a Consultant to Heron Therapeutics, and is on the Board of Directors of the Scientific Committee of Spectrum Pharmaceuticals, Odonate Therapeutics, and AmerisourceBergen, and owns stocks in Spectrum Pharmaceuticals, Odonate Therapeutics, LaJolla Pharma, Coherus Biosciences, and Heron Therapeutics.
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- Roila F, Molassiotis A, Herrstedt J, et al; for the participants of the MASCC/ESMO Consensus Conference Copenhagen 2015. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27(suppl 5):v119-v133.
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- Navari RM, Roeland EJ. Unscheduled hydrations: redefining complete response in chemotherapy-induced nausea and vomiting studies. Future Oncol. 2020;16:1863-1872.
- Ottoboni T, Gelder MS, O’Boyle E. Biochronomer technology and the development of APF530, a sustained release formulation of granisetron. J Exp Pharmacol. 2014;6:15-21.
- Gabrail N, Yanagihara R, Spaczyński M, et al. Pharmacokinetics, safety, and efficacy of APF530 (extended-release granisetron) in patients receiving moderately or highly emetogenic chemotherapy: results of two phase II trials. Cancer Manag Res. 2015;7:83-92.
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- Raftopoulos H, Cooper W, O’Boyle E, et al. Comparison of an extended-release formulation of granisetron (APF530) versus palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately or highly emetogenic chemotherapy: results of a prospective, randomized, double-blind, noninferiority phase 3 trial. Support Care Cancer. 2015;23:723-732.
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- Kong AH, Mistry P, Evans M, et al. Analysis of hydration and antiemetics policies in preventing cisplatin-related gastrointestinal and renal toxicities in low-risk human papillomavirus positive-oropharyngeal cancer (HPV+OPC) patients undergoing chemoradiation in De-ESCALaTE trial. J Clin Oncol. 2019;37(15_suppl):Abstract 6076.